KLF4 Genetic and Epigenetic Changes in Human Pancreatic Cancer

人类胰腺癌中的 KLF4 遗传和表观遗传变化

基本信息

批准号：
8110605
负责人：
KEPING XIE
金额：
$ 24.8万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8110605
关键词：
Ablation Accounting Affect Alternative Splicing Angiogenic Factor Animal Model Animals Apoptosis Behavior Cancer Biology Cancer Patient Characteristics Clinical Complement DNA Data Development EMSA Engineering Epigenetic Process Epithelial Cells Event Family Flow Cytometry Gene Mutation Gene Targeting Genes Genetic Goals Growth Human Hypermethylation In Vitro Investigation Lead Loss of Heterozygosity Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of pancreas Measures Mediating Messenger RNA Molecular Molecular Genetics Molecular Target Mus Mutation Neoplasm Metastasis Normal tissue morphology Northern Blotting Outcome Pancreas Pathogenesis Pathologic Pathway interactions Phenotype Polymerase Chain Reaction Production Protein Binding Protein Overexpression Proteins RNA Interference RNA Splicing Reporter Resources Reverse Transcription Role Signal Transduction Signal Transduction Pathway Specimen TdT-Mediated dUTP Nick End Labeling Assay Testing Therapeutic Time Tissues Tumor Suppressor Proteins Tumor Tissue Variant Vascular Endothelial Growth Factors Western Blotting Zinc Fingers base clinically relevant clinically significant density design in vivo malignant phenotype member mouse model mutant neoplastic cell overexpression pancreatic cancer cells promoter protein expression public health relevance transcription factor tumor tumor growth tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Our recent studies have shown that increased KLF4 protein expression suppressed the growth of human pancreatic cancer, whereas knockdown of KLF4 expression did the opposite. Moreover, we have identified three KLF4 alternative splice variants and a point-mutant KLF4 in human pancreatic cancer cells. Experimentally enforced expression of one of the splice variant, KLF41, promoted tumor growth. However, the underlying mechanisms for the impact of altered KLF4 expression and function on pancreatic cancer pathogenesis are unclear. We postulate that genetic and epigenetic changes of KLF4 impact its tumor suppressor function and contribute to pancreatic cancer pathogenesis. To test our hypothesis, we propose the following three specific aims. Specific Aim 1 will test the hypothesis that genetic and epigenetic alterations lead to altered KLF4 expression and function and affect pancreatic cancer clinical outcome. Genetic (mutation and LOH) and epigenetic (promoter hypermethylation and alternative splicing) changes of KLF4 and their clinical significance in pancreatic cancer pathogenesis will be determined. Specific aim 2 will test the hypothesis that aberrant KLF4 expression and function promotes tumor growth and metastasis. Impacts of altered KLF4 expression and function on the malignant phenotype with a focus on angiogenic phenotype of human pancreatic cancer cells will be determine using in vitro and animal models. Specific Aim 3 will test the hypothesis that altered KLF4 expression and function results in dysregulated Sp1 expression and the imbalanced expression and function of Sp1 and KLF4 leads to an increased expression of pro-angiogenic factors that are predominantly regulated by Sp1. Impacts of altered expression and function of KLF4 on the expression and function of Sp1 and its downstream molecules in human pancreatic cancer cells will be determined. These three specific aims are supported by our respective preliminary data and can be tested independently using our unique research resources, yet they are highly interrelated and support one another. We predict that completion of these studies will provide insightful information for the molecular genetic basis of pancreatic cancer pathogenesis and for identification of molecular targets to design effective therapeutic strategies. In the long term, our study also can lead to further investigation of the molecular mechanisms mediating disregulated KLF4 expression and function. PUBLIC HEALTH RELEVANCE: KLF4 is a newly identified putative tumor suppressor in gastrointestinal cancers. However, the critical role of KLF4 signaling in human cancer development and progression in general and human pancreatic cancer in particular is unclear.

描述（申请人提供）：我们最近的研究表明，增加KLF4蛋白表达可以抑制人类胰腺癌的生长，而敲低KLF4表达则起到相反的作用。此外，我们还在人胰腺癌细胞中鉴定了三种 KLF4 选择性剪接变体和一种点突变 KLF4。通过实验强制表达其中一种剪接变体 KLF41，可促进肿瘤生长。然而，KLF4 表达和功能改变对胰腺癌发病机制影响的潜在机制尚不清楚。我们假设 KLF4 的遗传和表观遗传变化影响其肿瘤抑制功能并有助于胰腺癌的发病机制。为了检验我们的假设，我们提出以下三个具体目标。具体目标 1 将检验遗传和表观遗传改变导致 KLF4 表达和功能改变并影响胰腺癌临床结果的假设。将确定 KLF4 的遗传（突变和 LOH）和表观遗传（启动子高甲基化和选择性剪接）变化及其在胰腺癌发病机制中的临床意义。具体目标 2 将检验异常 KLF4 表达和功能促进肿瘤生长和转移的假设。将使用体外和动物模型确定 KLF4 表达和功能改变对恶性表型的影响，重点是人胰腺癌细胞的血管生成表型。具体目标 3 将检验以下假设：KLF4 表达和功能的改变会导致 Sp1 表达失调，而 Sp1 和 KLF4 的表达和功能失衡会导致主要受 Sp1 调节的促血管生成因子的表达增加。将确定 KLF4 的表达和功能改变对人胰腺癌细胞中 Sp1 及其下游分子的表达和功能的影响。这三个具体目标得到了我们各自的初步数据的支持，并且可以使用我们独特的研究资源进行独立测试，但它们之间高度相关并相互支持。我们预测这些研究的完成将为胰腺癌发病机制的分子遗传学基础以及识别分子靶点以设计有效的治疗策略提供富有洞察力的信息。从长远来看，我们的研究还可以进一步研究介导 KLF4 表达和功能失调的分子机制。公共健康相关性：KLF4 是一种新发现的胃肠道癌症的推定肿瘤抑制因子。然而，KLF4 信号传导在人类癌症、特别是人类胰腺癌的发生和进展中的关键作用尚不清楚。